TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection.

A polymorphism causing deficiencies in Toll-interacting protein (TOLLIP), an inhibitory adaptor protein affecting endosomal trafficking, is associated with increased tuberculosis (TB) risk. It is, however, unclear how TOLLIP affects TB pathogenesis. Here we show that TB severity is increased in Tollip mice, characterized by macrophage- and T cell-driven inflammation, foam cell formation and lipid accumulation.

Toll-interacting protein inhibits transforming growth factor beta signaling in mouse lung fibroblasts.

Variations in the Toll-interacting protein (TOLLIP) gene have been identified in genome-wide association studies to correlate with risk of disease, mortality, and response to N-acetylcysteine therapy in idiopathic pulmonary fibrosis. Although TOLLIP is known to modulate innate immune responses, its relevance in organ fibrogenesis remains unknown. Prior work in the literature suggests TOLLIP dampens transforming growth factor beta (TGFβ) signaling in human cell lines.

Effect of lung pericyte-like cell ablation on the bleomycin model of injury and repair.

We previously showed that pericyte-like cells derived from the FoxD1-lineage contribute to myofibroblasts following bleomycin-induced lung injury. However, their functional significance in lung fibrosis remains unknown. In this study, we used a model of lung pericyte-like cell ablation to test the hypothesis that pericyte-like cell ablation attenuates lung fibrosis in bleomycin-induced lung injury.

The bioactivity of soluble Fas ligand is modulated by key amino acids of its stalk region.

We have previously reported that the 26-amino acid N-terminus stalk region of soluble Fas ligand (sFasL), which is separate from its binding site, is required for its biological function. Here we investigate the mechanisms that link the structure of the sFasL stalk region with its function. Using site-directed mutagenesis we cloned a mutant form of sFasL in which all the charged amino acids of the stalk region were changed to neutral alanines (mut-sFasL).

Pericyte-like cells undergo transcriptional reprogramming and distinct functional adaptations in acute lung injury.

We previously reported on the role of pericyte-like cells as functional sentinel immune cells in lung injury. However, much about the biological role of pericytes in lung injury remains unknown. Lung pericyte-like cells are well-positioned to sense disruption to the epithelial barrier and coordinate local inflammatory responses due to their anatomic niche within the alveoli.

Role of integrin alpha8 in murine model of lung fibrosis.

Background: Integrin α8 (ITGA8) heterodimerizes with integrin β1 and is highly expressed in stromal cells of the lung. Platelet-derived growth factor receptor beta (PDGFRβ+) cells constitute a major population of contractile myofibroblasts in the lung following bleomycin-induced fibrosis. Integrin α8β1 is upregulated in fibrotic foci in bleomycin-induced lung injury.

Ablation of Pericyte-Like Cells in Lungs by Oropharyngeal Aspiration of Diphtheria Toxin.

We demonstrated previously that FoxD1-derived cells in the lung are enriched in pericyte-like cells in mouse lung. These cells express the common pericyte markers and are located adjacent to endothelial cells. In this study, we demonstrate the feasibility of administering diphtheria toxin (DT) by oropharyngeal aspiration as an approach to ablating FoxD1-derived cells.

uPARAP function in cutaneous wound repair.

Optimal skin wound healing relies on tight balance between collagen synthesis and degradation in new tissue formation and remodeling phases. The endocytic receptor uPARAP regulates collagen uptake and intracellular degradation. In this study we examined cutaneous wound repair response of uPARAP null (uPARAP-/-) mice.

Proteomic landscape of bronchoalveolar lavage fluid in human immunodeficiency virus infection.

The lung is an important reservoir of human immunodeficiency virus (HIV). Individuals infected with HIV are more prone to pulmonary infections and chronic lung disorders. We hypothesized that comprehensively profiling the proteomic landscape of bronchoalveolar lavage fluid (BALF) in patients with HIV would provide insights into how this virus alters the lung milieu and contributes to pathogenesis of HIV-related lung diseases.

Role of lung pericytes and resident fibroblasts in the pathogenesis of pulmonary fibrosis.

Rationale: The origin of cells that make pathologic fibrillar collagen matrix in lung disease has been controversial. Recent studies suggest mesenchymal cells may contribute directly to fibrosis.

Objectives: To characterize discrete populations of mesenchymal cells in the normal mouse lung and to map their fate after bleomycin-induced lung injury.

Proteomic profiling of bronchoalveolar lavage fluid in critically ill patients with ventilator-associated pneumonia.

Rationale: Ventilator-associated pneumonia (VAP) is a common complication in patients with acute lung injury (ALI) and can lead to increased morbidity and mortality. Identifying protein profiles specific to VAP in bronchoalveolar lavage fluid (BALF) may aid in earlier diagnosis, elucidate mechanisms of disease, and identify putative targets for therapeutic intervention.

Methods: BALF was obtained from 5 normal subjects and 30 ALI patients: 14 with VAP (VAP(+)) and 16 without VAP (VAP(-)).

In vivo targeting of alveolar macrophages via RAFT-based glycopolymers.

Targeting cell populations via endogenous carbohydrate receptors is an appealing approach for drug delivery. However, to be effective, this strategy requires the production of high affinity carbohydrate ligands capable of engaging with specific cell-surface lectins. To develop materials that exhibit high affinity towards these receptors, we synthesized glycopolymers displaying pendent carbohydrate moieties from carbohydrate-functionalized monomer precursors via reversible addition-fragmentation chain transfer (RAFT) polymerization.

Effect of insulin-like growth factor blockade on hyperoxia-induced lung injury.

Insulin-like growth factor (IGF)-1 is increased in different models of acute lung injury, and is an important determinant of survival and proliferation in many cells. We previously demonstrated that treatment of mice with IGF-1 receptor-blocking antibody (A12) improved early survival in bleomycin-induced lung injury. We have now examined whether administration of A12 improved markers of lung injury in hyperoxia model of lung injury.

Short communication: adhesion pathways utilized by HIV-infected lymphocytes.

We recently reported a novel adhesion pathway in lymphocytes that is mediated by cyclin-dependent kinase (Cdk) 4 activity and mediates lymphocyte interactions with endothelial matrix. We now demonstrate that HIV-infected lymphocytes also use Cdk4 to mediate spontaneous adhesion to fibronectin and endothelial matrix. We further demonstrate that HIV-infected lymphocytes require Rap-1 activity for phorbol-stimulated adhesion.

Role of urokinase plasminogen activator receptor-associated protein in mouse lung.

Urokinase plasminogen activator receptor-associated protein (uPARAP, or Endo180) is a transmembrane endocytic receptor that mediates collagen internalization and degradation. uPARAP may be a novel pathway for collagen turnover and matrix remodeling in the lung. The function of uPARAP in lung injury has not been described.

Role of Cdk4 in lymphocyte function and allergen response.

We recently described a new adhesion pathway in lymphocytes that is dependent on Cyclin-dependent kinase (Cdk) 4 activity and mediates lymphocyte interactions with endothelial matrix. We showed that Cdk4(-/-) mice had impaired recruitment of lymphocytes following bleomycin model of acute lung injury. In this study, we characterized the development and function of hematopoietic cells in Cdk4(-/-) mice and assessed the response of Cdk4(-/-) mice to allergen challenge.

Inefficient cationic lipid-mediated siRNA and antisense oligonucleotide transfer to airway epithelial cells in vivo.

Background: The cationic lipid Genzyme lipid (GL) 67 is the current "gold-standard" for in vivo lung gene transfer. Here, we assessed, if GL67 mediated uptake of siRNAs and asODNs into airway epithelium in vivo.

Methods: Anti-lacZ and ENaC (epithelial sodium channel) siRNA and asODN were complexed to GL67 and administered to the mouse airway epithelium in vivo Transfection efficiency and efficacy were assessed using real-time RT-PCR as well as through protein expression and functional studies.

Protection of Cftr knockout mice from acute lung infection by a helper-dependent adenoviral vector expressing Cftr in airway epithelia.

We developed a helper-dependent adenoviral vector for cystic fibrosis lung gene therapy. The vector expresses cystic fibrosis transmembrane conductance regulator (Cftr) using control elements from cytokeratin 18. The vector expressed properly localized CFTR in cultured cells and in the airway epithelia of mice.

Regulation of human Clara cell 10 kD protein expression by chicken ovalbumin upstream promoter transcription factors (COUP-TFs).

Clara cell 10 kD protein (CC10) is expressed specifically in a portion of nonciliated airway epithelial cells. The molecular mechanisms that determine its high specificity are not clear. Transcription factors implicated in the regulation of CC10 in rodents do not show the same level of cell specificity.